Parkinson?s disease (PD) is a common progressive neurodegenerative disease affecting approximately 2 percent of the population over age 65 throughout the world. Evidence from studies of idiopathic PD suggests that it is a complex disease involving multiple genetic and environmental factors. We have developed a potential mouse model of idiopathic Parkinson?s disease in the Engrailed-i (En-i) knockout mouse, En aboutiM. Homozygous En about ih/d mice on the 129/Sv inbred strain display severe cerebellar hypoplasia and perinatal lethality. In contrast, on the C57B1/6J inbred strain, homozygous mice are viable and exhibit tremors and hesitant gate reminiscent of Parkinson?s disease. To further analyze the role of strain background on the En-i mutant phenotype we propose the following three specific aims: 1) further characterize the Parkinson?s disease phenotype of En-i deficient mice, 2) genetically map strain-specific modifier genes required to produce the PD phenotype in En-1hd mutant mice, and 3) analyze candidate modifier genes for strain-specific alterations that contribute to the PD phenotype. The discovery of new genes with a genetic link to PD will provide future targets for therapeutic intervention.